This invention pertains to a method of modulating neovascularization in an animal.
Neovascularization, or the formation of new blood vessels, is a highly complex and tightly regulated biological process. Neovascularization is normally not continuously required on a large scale in adult animals, thus the process for forming blood vessels is often quiescent except in instances of injury and wound repair. When vascularization is not stringently controlled, serious pathologies can result. For example, reduced vascularization of target tissues is associated with ischemic damage, vascular diseases, necrosis, and muscle wasting. Increased vascularization is associated with, for instance, tumor growth, edema, and diseases of eye, such as diabetic retinopathy and the exudative form of age-related macular degeneration, which are major causes of blindness worldwide.
Several strategies for controlling vascularization have been proposed. Angiogenic or anti-angiogenic proteins have been administered to an animal to modulate neovascularization. However, it is difficult to target the administration of proteins to tissues such that widespread neovascularization does not occur. In addition, the half-life of some angiogenesis-influencing factors is relatively low, thereby complicating administration of appropriate dosages of peptides to achieve a desired effect. Delivery of an angiogenic or an anti-angiogenic agent to target tissues has also been achieved using gene transfer methods with encouraging results. For example, delivery of vascular endothelial growth factor (VEGF) has promoted improved perfusion of cardiac tissue and ischemic limbs (see, for example, Isner et al., The Lancet, 348, 370-373 (1996). While perfusion of the target tissue is improved, a more efficient means of modulating neovascularization is needed. In addition, some factors have reduced efficacy under certain conditions. For example, preclinical data suggest that VEGF is less effective in aged individuals.
In view of the above, there exists a need in the art for an alternative and efficient means of modifying vascularization in an animal. The present invention provides such a method. This and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a method of modulating neovascularization in an animal. The method comprises administering to the animal two or more nucleic acid sequences, each nucleic acid sequence encoding at least one angiogenesis-modulation factor that acts upon a different angiogenic process. Each nucleic acid sequence is under the control of separate promoters having different expression profiles. The nucleic acid sequences are expressed to produce the angiogenesis-modulation factors to modulate neovascularization in the animal. The angiogenesis-modulation factor can be an angiogenesis-promoting factor such that neovascularization is induced in the animal. Alternatively, the angiogenesis-modulation factor is an angiogenesis inhibitor and neovascularization is inhibited or reduced in the animal.